Oxidative stress has been implicated in the pathogenesis of acute and chronic liver injury in a variety of pathophysiological conditions such as hepatotoxin exposures, intrahepatic cholestasis, alcoholic liver injury, liver ischemia/reperfusion injury and viral hepatitis (Stehbens W E. Exp Mol. Pathol. 2003; 75(3): 265-76. Jaeschke H et al. Toxicol-Lett. 2003; 144(3): 279-88. McDonough K H. Toxicology. 2003; 189(1-2): 89-97. Jaeschke H et al. J Clin Invest. 1988; 81(4): 1240-6). Overproduction of reactive oxygen species (ROS) and nitrogen species (RNS), along with significant decrease of antioxidant defense in these pathological conditions, impairs various cellular functions through the processes of lipid peroxidation, protein oxidation and nucleic base oxidation. Lipid peroxidation, for example, causes changes in the physical and chemical properties of cellular membranes, thus altering their fluidity and permeability, leading to impairment in membrane signal transduction and ion exchange, resulting in swelling, cytolysis and finally cell death. The oxidation of proteins and DNA also relates directly to cellular dysfunction and death (Fang Y Z et al. Nutrition. 2002; 18(10): 872-9).
Accordingly, effects of antioxidants or free radical scavengers have been widely tested for the prevention and treatment of acute and chronic liver injuries. In some of those studies, antioxidants have shown beneficial effects, specifically for prevention and treatment of chronic liver injury (Parola M et al. Hepatology. 1992; 16(4):1014-21. Halim A B, et al. Ann Clin Biochem. 1997; 34 (Pt 6):656-63. Garcia-Ruiz C, et al. Hepatology. 1995; 21(1):207-14. Mato J M et al. 3 Hepatol. 1999; 30(6):1081-9. Lieber et al. Hepatology. 1990; 11(2):165-72. Bruck R et al. J Hepatol. 2001; 35(4): 457-64. Bruck R et al. J Hepatol. 2004; 40(1): 86-93). However, the efficacy of antioxidant treatment in acute liver injury with a single antioxidant has been less clear (Baron V et al. Biochim Biophys Acta. 1999; 1472(1-2):173-80). Currently available antioxidant treatments are deficient for the treatment of acute liver injury. Furthermore, currently available antioxidant therapies do not address secondary events resulting from the injury such as insulin resistance.